Synthesis and biological evaluation of chromanone-based derivatives as potential anti-neuroinflammatory agents.

As a privileged scaffold, chromanone has been extensively introduced in the design of drug leads with diverse pharmacological features, particularly in the area of inflammatory diseases. Herein, the preparation of chromanone-based derivatives (4a-4i) was smoothly achieved, and their structures were characterized using 1H NMR, 13C NMR, and ESI-HRMS spectroscopy techniques. Out of them, analogue 4e exhibited the most potent inhibitory capacity against the NO release and iNOS expression, without apparent cytotoxicity. Our observations showed that 4e could dramatically prevent the translocation of NF-κB from the cytoplasm to nucleus, and decrease the production of proinflammatory cytokines TNF-α, IL-6 and IL-1ß in LPS-induced BV-2 cells. Mechanistically, 4e significantly deactivated NF-κB by disturbing TLR4-mediated TAK1/NF-κB and PI3K/Akt signaling cascades. Consistent with the in vitro study, 4e could effectively mitigate the inflammation response of hippocampal tissue in LPS-induced mouse model by inhibiting microglial activation. Collectively, these results revealed 4e as a prospective neuroprotective candidate for the therapy of neuroinflammation-related disorders.

The NDUFV2 gene silencing inhibits the proliferation of two drug-resistant cancer cell lines.

BACKGROUND: Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. It is unlikely that there will ever be a single cure for cancer, but the development of molecular biology and cell biology has brought new options for cancer treatment. Our research group found in the preliminary experiments that AAs exhibited significant anti-tumor activity. Studies also showed that AAs exhibited varying degrees of downregulation effects on the expression of the NDUFV2 gene in the MCF-7/ADR and SMMC-7721/ADR cell lines. However, there is no relevant report on the role of this gene expression during the growth process of drug-resistant tumor cells. To address possible objections, this paper aims to investigate the effect of NDUFV2 gene silencing on the proliferation of the MCF-7/ADR and SMMC-7721/ADR cell lines. RESULTS: The interfering plasmids pPLK/GFP+Puro-NDUFV2 shRNA-3 and shRNA-2 inhibited the NDUFV2 gene and protein expression most significantly in MCF-7/ADR and SMMC-7721/ADR cells, respectively. NDUFV2 gene silencing could effectively inhibit the proliferation of both cell lines. The inhibition rates for MCF-7/ADR were 67.31%, 73.02%, and 69.76% at 24 h, 48 h, and 72 h, while that for SMMC-7721/ADR were 68.89%, 71.97%, and 74.40% at 24 h, 48 h, and 72 h, respectively. The inhibition rate of SMMC-7721/ADR cell proliferation was positively correlated with time. CONCLUSIONS: Interference with the NDUFV2 gene may significantly inhibit the proliferation of MCF-7/ADR and SMMC-7721/ADR cells. This study is the pioneer to investigate that the NDUFV2 gene has been associated with the activity of inhibiting tumor cell proliferation, suggesting that the NDUFV2 gene may become a potential target for the study of tumor genesis and the development of antineoplastic drugs.

Three new antitumor annonaceous acetogenins from the seeds of Annona squamosa.

Two new annonaceous acetogenins squamocin P (2) and annosquatin III (3) and one new ACG precursor dieporeticenin B (1) along with five known precursors (4-8) were isolated from the seeds of Annona squamosa. Their structures were ascertained by chemical methods and various spectral evidences. These compounds showed inhibitory effects against three multidrug-resistant (MDR) cancer cell lines. Compound 2 and 3 displayed selective cytotoxicity against SMMC 7721/T (IC50 0.435 and 1.79 µM) and MCF-7/ADR (IC50 values 3.34 and 4.04 µM).

Antitumor activity of Annona squamosa seed oil.

CONTEXT: Custard apple (Annona squamosa Linn.) is an edible tropical fruit, and its seeds have been used to treat "malignant sore" (cancer) and other usage as insecticide. A comparison of extraction processes, chemical composition analysis and antitumor activity of A. squamosa seed oil (ASO) were investigated. MATERIALS AND METHODS: The optimal extraction parameters of ASO were established by comparing percolation, soxhlet, ultrasonic and SFE-CO2 extraction methods. The chemical composition of fatty acid and content of total annonaceous acetogenins (ACGs) of ASO was investigated by GC-MS and colorimetric assay, and anti-tumor activity of ASO was tested using H22 xenografts bearing mice. RESULTS: The optimal extraction parameters of ASO were obtained as follows: using soxhlet extraction method with extraction solvent of petroleum ether, temperature of 80°C, and extraction time of 90min. Under these conditions, the yield of ASO was 22.65%. GC-MS analysis results showed that the main chemical compositions of fatty acid of ASO were palmitic acid (9.92%), linoleic acid (20.49%), oleic acid (56.50%) and stearic acid (9.14%). The total ACGs content in ASO was 41.00mg/g. ASO inhibited the growth of H22 tumor cells in mice with a maximum inhibitory rate of 53.54% by oral administration. Furthermore, it was found that ASO exerted an antitumor effect via decreasing interleukin-6 (IL-6), janus kinase (Jak) and phosphorylated signal transducers and activators of transcription (p-Stat3) expression. DISCUSSION AND CONCLUSION: The results demonstrated that ASO suppressed the H22 solid tumor development may due to its main chemical constituents unsaturated fatty acid and ACGs via IL-6/Jak/Stat3 pathway. ASO may be a potential candidate for the treatment of cancer.

Metabolomics study on the toxicity of Annona squamosa by ultraperformance liquid-chromatography high-definition mass spectrometry coupled with pattern recognition approach and metabolic pathways analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Annona squamosa Linn (Annonaceae) is a commonly used and effective traditional Chinese medicine (TCM) especially in the South China. The seeds of Annona squamosa Linn (SAS) have been used as a folk remedy to treat "malignant sores" (cancer) in South of China, but they also have high toxicity on human body. AIM OF THE STUDY: To discover the potential biomarkers in the mice caused by SAS. MATERIALS AND METHODS: We made metabonomics studies on the toxicity of SAS by ultraperformance liquid-chromatography high-definition mass spectrometry coupled with pattern recognition approach and metabolic pathways analysis. RESULTS: The significant difference in metabolic profiles and changes of metabolite biomarkers between the Control group and SAS group were well observed. 11 positive ions and 9 negative ions (P<0.05) were indicated based on UFLC-QTOF-HDMS. The metabolic pathways of SAS group are discussed according to the identified endogenous metabolites, and eight metabolic pathways are identified using Kyoto Encyclopedia of Genes and Genomes (KEGG). CONCLUSIONS: The present study demonstrates that metabonomics analysis could greatly facilitate and provide useful information for the further comprehensive understanding of the pharmacological activity and potential toxicity of SAS in the progress of them being designed to a new anti-tumor medicine.

[Structure activity relationship of annonaceous acetogenins against multidrug resistant human lung cancer cell line A549/Taxol in vitro].

10 kinds of annonaceous acetogenins were selected for antitumor activity testing against human lung cancer cell line A549/Taxol and the structure activity relationship was analyzed.MTT assay was used to detect the inhibitory activities of 10 kinds of annonaceous acetogenins and positive drugs against A549/Taxol cells, respectively uvariamicin-Ⅲ(1), uvariamicin-Ⅱ(2), annosquacin D(3), desacetyluvaricin(4), annosquatin A(5), squamostatin D(6), bullatacin(7), squamocin(8), motrilin(9), annosquatin B(10), verapamil and cisplatin. Annonaceous acetogenins showed significant inhibitory activities against A549/Taxol cells, and were more potent than the positive drug verapamil and cisplatin.The more carbon atoms between the tetrahydrofuran ring and the lactone ring of annonaceous acetogenins exhibited more potency.Besides,ACGs with two substituted hydroxyl showed more potency than the compounds with three substituted hydroxyl in the bis-adjacent-THF ACGs. Furthermore, ACGs with three substituted hydroxyl showed more potency than the compounds with four substituted hydroxyl among the no bis-adjacent-THF ACGs.